Bioinspired Total Syntheses of Skeletally Diverse Lycopodium Alkaloids

The phlegmarine skeleton is widely recognized as a key biogenetic intermediate in Lycopodium alkaloids. On this basis, we designed a phlegmarine-derived common intermediate that enables the collective, asymmetric total syntheses of 12 Lycopodium alkaloids with five distinct carbon skeletons. This intermediate was prepared on a decagram scale using commercially available (R)-pulegone in an eight-step sequence, with a stereoselective Michael addition as a key transformation. Subsequent selective carbon–carbon bond formation of this pivotal intermediate─(C4–C10, C4–C12, C1–C14, and C4–C13)─along with a skeletal rearrangement, delivered five frameworks: the huperzimine, lycodine, lycopodine, and phlegmarine classes, which were represented by (−)-hupserrine A, (−)-β-obscurine, (−)-lycopodine, (−)-cermizine B, and the lyconadin C diastereomer, respectively. Furthermore, we developed the first asymmetric total synthesis of (−)-hupserrine A, which bears a complex [6/6/5/6/7] pentacyclic cage structure and inhibits the 5-HT3A receptor (IC50 = 10.6 μM).